Neurofibromatosis type 1 (NF1) is the most common single gene disorder to affect the human nervous system. It is transmitted genetically in an autosomal dominant manner. NF1 affects approximately 1.5 million people worldwide and there is no racial, ethnic, or geographic predilection for the disorder. NF1 is caused by mutation in the NF1 gene, which produces neurofibromin, a tumor suppressor. A high spontaneous mutation rate (50%) at the NF1 locus insures that the disorder is unlikely to decrease significantly in the population due to genetic screening.
People affected by NF1 are at increased risk for developing a variety of tumors of the nervous system, including dermal, subdermal and plexiform neurofibromas; optic pathway astrocytomas, and malignant peripheral nerve sheath tumors (“MPNST”), and for learning disability, scoliosis and certain forms of leukemia. These tumors may cause disfigurement, nervous system damage and chronic pain. Dermal neurofibromas are the commonest lesion in NF1 and occur in 90% of affected individuals. Dermal neurofibromas are typically small (less than 2 cm in diameter), multiple and first develop during puberty. They are typically high in collagen content, have very low metabolic activity, and, as opposed to plexiform neurofibromas, never undergo malignant degeneration. There has never been a reported case of malignant degeneration in a dermal neurofibroma spontaneously or in patients who have received regional radiotherapy for various malignancies or who have received chemotherapy for malignancy.
Certain patients may develop some of the same disfiguring signs that are associated with Elephant Man's disease, a separate disorder originally thought to be NF1. The only treatment at the present time is surgical removal. However, tumors often cannot be removed without causing major neurologic and/or cosmetic problems, and frequently re-grow. They are not responsive to radiotherapy or to known chemotherapeutic agents.
Cutaneous and subcutaneous neurofibromas may develop at any time in life, but their numbers are usually small before puberty. The total number of neurofibromas seen in adults varies from just a few to thousands. Additional cutaneous and subcutaneous neurofibromas develop throughout life, although the rate of appearance may vary greatly from year to year. Other than an actual cure for the condition, an effective non-surgical treatment for dermal neurofibromas is the single highest priority for the 100,000 people in the U.S. affected by NF1. Dermal neurofibromas cause significant disfigurement, pain, psychological and financial stress and should be considered a major unmet medical need in this population. Development of a local treatment for dermal neurofibromas has not previously been explored because of several factors including the relatively low proliferation index with respect to other tumors, and the fact that the tumors reside slightly deeper in the skin especially when compared to basal and squamous cell carcinomas. This local treatment encompasses both topical treatment and intralesional or intradermal treatment at the site of the neurofibroma. Therefore, although such a local treatment of these dermal neurofibromas would be a valuable treatment for an unmet medical need, work has not been done in this area previously.